This is the fourth project in a Centers of Cancer Nanotechnology Excellence (CCNE) application entitled Emory-GA Tech Nanotechnology Center for Personalized and Predictive Oncology." Its primary objective is to develop spectroscopic nanoparticle tags based on surface-enhanced Raman scattering (SERS) for cancer molecular profiling. These multiplexed Raman nanotags are expected to have broad applications in cancer histopathology, biomarker detection, and molecular and cellular imaging. The proposed research builds on recent advances in single-molecule and single-nanoparticle SERS in general, and glass-coated metal nanoparticles loaded with Raman reporters (SERS nanotags) in particular, that have offered unique advantages and opportunities for cancer applications. These unique features include: (i) interrogation in the near-infrared (NIR) spectral region, allowing use with H&E stains and imaging instruments available in . diagnostic settings;(ii) excellent detection sensitivity for sensitive and quantitative measurements;(iii) multiplexing capability for simultaneous assays of 10 or more different cancer markers;and (iv) small particle size and "non-sticky" surface for improved spatial resolution and biochemical selectivity as compared with conventional immunohistochemical (IHC) reagents. In this project, we will merge Ramanbased nanoparticle tags with histopathology to develop novel assays with potential for rapid adoption in clinical diagnostic settings. A major clinical focus will be on renal cell carcinoma (RCC) and prostate cancer. Renal carcinoma is the most common malignancy of adult kidney and comprises 3% of all human cancers, while prostate carcinoma is the most common non-skin cancer and second-leading cause of cancer death in men. Diagnostic classification of renal tumors is critically important, because the major histopathologic subtypes are associated with distinct clinical behavior and optimal management. However, light microscopic diagnosis is difficult and subjective because tumor subtypes share many histopathologic features. Moreover, hematoxylin &eosin, the gold standard stain for light microscopy, provides no information on underlying molecular abnormalities. Our gene expression analyses have identified panels of molecular markers that distinguish renal tumor subtypes, which can be applied to SERS-based molecular differentiation of renal tumors. The diagnosis and treatment of prostate cancer also depends on panels of molecular biomarkers, and our groups have identified biomarker panels that define cases with a "lethal phenotype" that may require unique therapy. If successful, this project will make a major impact in translating nanotechnology and biomarkers to molecular tumor detection, diagnosis, and prognosis. Its potential practical outcomes include core-shell SERS nanoparticle tags with conjugated tumor targeting ligands, (b) a new class of small atomic nanoclusters with tunable light emission properties, and (c) translation of nanotechnology to renal and prostate cancer care.